This application is a 371 of PCT/FR99/00593 filed Mar. 17, 1999.
The present invention relates in general to a novel methylbiphenyl derivative, to a process for its preparation and to its use as a synthetic intermediate.
More specifically, a subject of the invention is o-tolylbenzaldoxime of formula: 
this compound being considered in the form of its individual isomers or mixtures thereof.
The oxime derivative of formula I, referred to hereinbelow as OTBO, has been found to be particularly useful as an intermediate product, in particular for the preparation of o-(p-tolyl)benzonitrile, which is referred to hereinbelow as OTBN.
The latter compound may itself be widely used as a particularly advantageous intermediate, since it is the key intermediate in the synthesis of many active principles in medicinal products acting in particular against hypertension via an angiotensin II inhibitory mechanism.
OTBN was disclosed for the first time in patent EP 253 310 and a certain number of processes for synthesizing it have recently been proposed.
One of the processes which appears to be the most suitable for preparing OTBN was disclosed in patent EP 566 488. It consists of the reaction between an o-halobenzonitrile and a p-tolylmagnesium halide in the presence of a manganous salt, preferably MnCl2. However, this method produces as a reaction by-product from 6.5% to 10% by weight of 4,4xe2x80x2-dimethylbiphenyl, referred to hereinbelow as bis-tolyl, resulting from the self-condensation of the p-tolylmagnesium halide.
In the context of the invention, the possibility of preparing OTBN via one of its potential precursors, in this instance o-(p-tolyl)benzaldoxime, was investigated with a view to solving the above problem.
To this end, attempts were made to apply a process similar to that of patent EP 253 310 also using p-tolylmagnesium bromide.
However, tests performed starting with 2-chlorobenzaldoxime and 3.5 equivalents of p-tolyl-magnesium bromide, the reaction taking place in the presence of 0.36 equivalent of MnCl2 in tetrahydrofuran at 90xc2x0 C. and for 8 hours, did not produce the expected coupling reaction but rather the massive production of bis-tolyl.
The search for a process for preparing OTBN starting, for example, with the corresponding oxime, which is itself obtained in an advantageous manner and is free of the drawbacks mentioned above, remains of unquestionable interest.
It has now been found, surprisingly, that o-(p-tolyl)benzaldoxime can be obtained in excellent yields and with less than 6% bis-tolyl by-product by a coupling reaction using p-tolylmagnesium bromide and, rather than 2-chlorobenzaldoxime, an N-substituted 2-halobenzaldimine, so as to form an N-substituted o-(p-tolyl)benzaldimine which can readily be converted into the desired oxime.
According to the invention, this oxime of formula I is obtained by reacting a hydroxylamine salt with a benzaldimine derivative of general formula: 
in which R represents a linear or branched C3-C7 alkyl group or a C3-C7 cycloalkyl group, this compound of formula II being considered in the form of individual isomers or a mixture thereof, which gives the desired compounds.
This reaction usually takes place at a temperature of between 0xc2x0 C. and 10xc2x0 C., preferably between 0xc2x0 C. and 5xc2x0 C., and in an aprotic solvent.
In the context of the present invention, the expression xe2x80x9caprotic solventxe2x80x9d means a solvent such as an ether, generally an aliphatic or alicyclic ether, for example tetrahydrofuran, methyl tert-butyl ether, dibutyl ether or dioxane, an aliphatic or aromatic hydrocarbon, such as benzene, toluene or a xylene, or a halogenated hydrocarbon, such as dichloromethane, dichloroethane, chloroform or tetrachloroethane.
However, an ether is preferably used as solvent, for example tetrahydrofuran.
Moreover, the hydroxylamine salt, such as the hydrochloride or, preferably, the sulphate, is used in a proportion of from 1.5 to 2.5 molar equivalents per molar equivalent of benzaldimine derivative of formula II.
According to this method, OTBO can be obtained in yields of about 90% to 93% by weight.
The methylbiphenyl derivatives of formula II are novel and, in this respect, constitute another subject of the invention, whether they are in the form of individual isomers or a mixture thereof.
Consequently, the invention also relates, as novel intermediate products, to the benzaldimine derivatives of formula II in which R represents a linear or branched C3-C7 alkyl group or a C3-C7 cycloalkyl group, these benzaldimine derivatives being in the form of individual isomers or mixtures thereof.
Among these compounds of formula II, those in which R represents a tert-butyl group or, better still, a cyclohexyl group constitute preferred compounds.
The compounds of formula II can be prepared by reacting, in the presence of an inorganic manganese derivative, a benzaldimine derivative of general formula: 
in which R has the same meaning as above and Hal represents a halogen atom such as chlorine or bromine, this compound being in the form of individual isomers or mixtures thereof, with a p-tolylmagnesium halide, such as p-tolylmagnesium chloride or bromide, giving the desired compounds.
This coupling reaction is generally carried out in a suitable solvent and at a temperature of between xe2x88x9210xc2x0 C. and the reflux temperature, preferably at the reflux temperature of the reaction medium.
The solvent usually envisaged is a compound of ether type such as an aliphatic or alicyclic ether, for example tetrahydrofuran, methyl tert-butyl ether, dibutyl ether or dioxane.
However, tetrahydrofuran is a preferred solvent.
In addition, the p-tolylmagnesium halide is generally used in excess, in particular in a proportion of from 1 to 2 molar equivalents per molar equivalent of compound of formula II, usually in a proportion of about 1.5 equivalents.
The inorganic manganese derivative is used in the reaction in a proportion of from 0.1 to 0.5 molar equivalent per molar equivalent of benzaldimine derivative of formula II, preferably from 0.15 to 0.30 molar equivalent.
This derivative is generally a manganese salt or oxide, but more particularly a manganous salt or manganous oxide. However, the manganous salt preferably corresponds to MnCl2 or MnCl4Li2, it being possible for the latter to be formed in situ by adding two molar equivalents of LiCl and one molar equivalent of MnCl2.
In this way, the compounds of formula II can be obtained in yields of at least 85% and with less than 6% bis-tolyl derivative.
For example, the preparation of o-(p-tolyl)-N-cyclohexylbenzaldimine starting with 0.4 mol of 2-chloro-N-cyclohexylbenzaldimine, 0.15 molar equivalent of MnCl2 and 1.5 molar equivalents of p-tolylmagnesium chloride in tetrahydrofuran for 1 hour gave, along with an excellent yield of OTBN, only 5.5% bis-tolyl relative to the starting imine.
As regards the benzaldimine derivatives of formula III, these can be prepared by reaction, at a temperature between room temperature and the reflux temperature and in an aprotic solvent, preferably an ether, between a 2-chloro- or 2-bromobenzaldehyde and an amine of general formula:
Rxe2x80x94NH2xe2x80x83xe2x80x83IV
in which R has the same meaning as above, thus giving the desired compounds.
Since this reaction proceeds with the formation of water, it may be advantageous to carry it out in the presence of an agent for dehydrating the reaction medium, such as anhydrous magnesium sulphate.
As indicated above, the oxime derivative of formula I can be used to prepare OTBN.
Consequently, the invention relates to o-(p-tolyl)benzaldoxime as an intermediate for the final synthesis of OTBN.
Thus, OTBN can be obtained starting with the oxime derivative of formula I, for example by subjecting it to the action of a dehydrating agent.
The resulting reaction is usually carried out at a temperature of between room temperature and the reflux temperature of the medium, and in an aprotic solvent, preferably an ether such as tetrahydrofuran.
In the context of the invention, the expression xe2x80x9cdehydrating agentxe2x80x9d means an agent capable of converting the oxime function into a nitrile function, such as, for example, formic acid, phosphorus pentoxide, phosphorus oxychloride, pyridine or dicyclohexylcarbodiimide.
In addition, the dehydration reaction usually takes place in an aprotic solvent, preferably and advantageously in an ether such as, for example, tetrahydrofuran, and at a temperature of between room temperature and the reflux temperature, preferably at the reflux temperature of the reaction medium.
However, this dehydration reaction can be undertaken in the absence of solvent, the dehydrating agent itself acting as the solvent. Such is the case in particular for formic acid, which can be used both as dehydrating agent and as solvent in the context of the invention.
According to the above method, OTBN is obtained in yields of purified and crystallized product of greater than 85%, generally of about 90% to 95%, starting from OTBO.
The oxime of formula I and the benzaldimine derivatives of formula II involved in the final synthesis of OTBN can be used after isolation from the reaction medium in which they are formed.
Advantageously and preferably, however, OTBN is prepared in the same medium in which OTBO is formed, without the latter being isolated.
Consequently, the invention also relates to the preparation of OTBN starting with a benzaldimine derivative of formula II: either:
(a) by reacting this imine in an aprotic solvent with a hydroxylamine salt at a temperature of between 0xc2x0 C. and 10xc2x0 C., so as to form, transiently and without isolation, the oxime of formula I, which is treated with a dehydrating agent at a temperature of between room temperature and the reflux temperature, giving the desired compound; or:
(b) by reacting this imine with hydroxylamine-O-sulphonic acid (H2Nxe2x80x94Oxe2x80x94SO3H) in a two-phase medium formed from water and from an aprotic solvent and at a temperature of between room temperature and the reflux temperature, in order to obtain, transiently and without isolation, the oxime of formula I as a mixture with OTBN, this mixture being treated with a dehydrating agent at a temperature of between room temperature and the reflux temperature, giving the desired compound. This method, which usually takes place in an aprotic solvent, first gives a transient mixture of OTBN/OTBO, generally a mixture of 55% to 75% by weight of OTBN/45% to 25% by weight of OTBO, followed by OTBN itself in an overall yield of greater than 90% and less than 6% of bis-tolyl compound; or:
(c) by hydrolysing this imine, in an aprotic solvent, to give o-(p-tolyl)benzaldehyde, which is reacted with a hydroxylamine salt at a temperature of between 0xc2x0 C. and 10xc2x0 C., which gives, transiently and without isolation, the oxime of formula I, which is treated with a dehydrating agent at a temperature of between room temperature and the reflux temperature of the medium, giving the desired compound.
According to alternative embodiments, OTBO and thereafter OTBN can be prepared starting with the imine derivatives of formula III without isolating the intermediate products formed.
For example, an imine derivative of formula III under consideration is reacted, in an ether such as tetrahydrofuran, with a p-tolylmagnesium halide in the presence of an inorganic manganese derivative and, generally, at a temperature of between xe2x88x9210xc2x0 C. and the reflux temperature, to form a benzaldimine derivative of formula II, which is then converted, without isolation from its reaction medium, into OTBO of formula I and then into OTBN according to one of the methods (a), (b) and (c) above.